Molecular Basis of the Brindled Mouse Mutant (Mobr): A Murine Model of Menkes Disease

• Published in: Human molecular genetics 1997-07, Vol.6 (7), p.1037-1042
• Main Authors: Grimes, Andrew, Hearn, Catherine J., Lockhart, Paul, Newgreen, Don F., Mercer, Julian F. B.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Amino Acid Sequence; Animals; Biological and medical sciences; Blotting, Western; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cation Transport Proteins; Conserved Sequence; Copper-transporting ATPases; Humans; Kidney - metabolism; Kidney Tubules, Distal - metabolism; Kidney Tubules, Proximal - metabolism; Medical sciences; Menkes Kinky Hair Syndrome - genetics; Metabolic diseases; Metals (hemochromatosis...); Mice; Mice, Mutant Strains; Molecular Sequence Data; Mutation; Other metabolic disorders; Recombinant Fusion Proteins; Sequence Deletion
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/6.7.1037

The brindled mouse mutant (Mobr) is the closest animal model of the human genetic copper deficiency, Menkes disease, which is presumed to be due to a mutation at the X-linked mottled locus (Mo). The mutant mice are hypopigmented and die at around 15 days after birth, but can be saved by treatment with copper before the 10th postnatal day. Menkes disease has been shown to be due to mutations of the gene ATP7A which encodes P-type ATPase (referred to here as MNK). MNK is likely to function in copper efflux from cells, but the full range of its biological activity is not fully understood. The nature of the mutation in the brindled mouse is of importance in our understanding of the role of MNK and for devising treatment strategies for Menkes disease. Here we show that the brindled mouse has a deletion of two amino acids in a highly conserved, but functionally uncharacterized, region of Mnk. Comparison with the Ca ATPases suggests this region may be involved in conformational changes associated with the E1/E2 transition fundamental to the action of P-type ATPases. We also describe the first Western blot data for Mnk in tissues, and these show normal levels of Mnk in mutant and brindled kidneys but none in liver. In the kidney, immunohistochemistry demonstrated Mnk in the proximal and distal tubules, the distribution is identical in mutant and normal. This distribution is consistent with Mnk being involved in copper resorption from the urine.